An estimated 14 million Americans have diabetes, a disease in which the body does not produce or respond properly to insulin. The resulting high blood glucose concentration levels (also referred to as blood glucose level or blood-sugar levels) can cause severe damage to the heart, blood vessels, kidneys, eyes and nerves. If untreated, diabetes can lead to death in an unexpectedly short period of time. People with diabetes must balance diet, exercise and medication (e.g., insulin, which can be taken orally or by injections) in order to maintain their blood glucose levels as close as possible to normal levels. Insulin pumps have been developed to enable continuous administration of insulin to a diabetic.
Regardless how insulin is administered to a diabetic, it is very important to continually monitor the blood glucose level to avoid the problems that arise from low glucose levels as well as those that arise from excessive glucose levels. Therefore, diabetics have to test their blood glucose levels frequently (as often as six times a day) in order to maintain a proper level of insulin in their blood.
Several different techniques have been developed for measuring blood glucose concentration levels. A change in blood glucose level affects the index of refraction and the absorbance spectrum of the blood. For example, in U.S. Pat. No. 4,704,029, discussed in more detail below, this change in the index of refraction of blood alters the fraction of light reflected at an interface in contact with the blood being tested. This technique is not amenable to a non-invasive method of detecting a person's blood glucose level. Several references, discussed below, utilize absorbance spectroscopy to measure the glucose concentration in a patient's blood. Unfortunately, because of the strong level of absorption of water at the wavelength of infrared absorption peaks for blood glucose, these techniques result in small output signals so that there is a smaller than desired signal-to-noise ratio for such tests.
Infrared absorption spectroscopy has long been used for the identification of unknown organic and biological substances in aqueous solutions. This technique is based upon the fact that all molecules exhibit, to some extent, their own unique oscillatory motions characterized by specific resonance absorption peaks in the infrared portion of the electromagnetic spectrum. These characteristic absorption peaks are caused by the resonant vibrational and rotational oscillations of the molecules themselves. In several references discussed in more detail below, absorption spectra are used to monitor changes in blood glucose levels. These resonant vibrational modes can also be utilized to implement fluorescence techniques for measuring blood glucose levels.
In U.S. Pat. No. 4,055,768 entitled Light Measuring Apparatus issued to Nathan S. Bromberg on Oct. 25, 1977, the level of zinc protoporphyrin in blood is detected by smearing a blood sample on a slide and illuminating this sample with pulsed light that induces fluorescent emission from the zinc protoporphyrin. Synchronous detection is used to measure the intensity of the pulsing fluorescent light emitted from these zinc protoporphyrin molecules.
In U.S. Pat. No. 4,704,029 entitled Blood Glucose Monitor, issued to Alan Van Heuvelen, a blood glucose monitor is presented that is particularly applicable for use as an implant for controlling an insulin pump. This glucose monitor measures the glucose level of blood by utilizing a refractometer which measures the index of refraction of blood adjacent to an interface with a transparent surface of the refractometer. Within this implanted monitor, light is directed at a transparent interface that is in contact with the diabetic's blood. The angle of incidence is near the critical angle of total internal reflection, so that the small changes in the index of refraction of blood caused by changes in the blood glucose level will significantly alter the fraction of light reflected from this surface. In order to eliminate a similar change in the amount of reflected light due to changes in the concentration of albumin in the diabetic's blood, two light beams of unequal wavelengths are each directed at the interface at an angle near it's associated critical angle.
The problem with this proposed technique is that it is not specific. The index of refraction of blood is affected by numerous chemical substances in blood, only one of which is the blood glucose level. Therefore, a change in this index of refraction may not indicate a change in the blood glucose level.
The usual procedure for testing blood glucose levels involves pricking a finger to obtain a small sample of blood for analysis. In addition to the unwelcome pain, frequent finger-pricks of a person with diabetes can produce inflammation and/or callousing of that person's fingers. Unfortunately, although the frequent finger pricks are avoided by use of an implanted monitor, not only must the diabetic be subjected to the discomfort of implanting such a monitor, these monitors are often attacked by the body in a manner that degrades device operation. Because of this, the diabetic might require a succession of such implants. Thus, a portable, non-invasive, inexpensive, reliable blood glucose sensor is badly needed to enable diabetics to take better care of themselves without having to draw blood each time they need to check their blood glucose levels.
Over the years, many purportedly non-invasive methods of monitoring blood glucose have been proposed. For example, in the following three U.S. patents, a light beam is directed through a person's eye to monitor that person's blood glucose level. In U.S. Pat. No. 3,963,019 entitled Ocular Testing Method and Apparatus issued to Quandt on Jun. 15, 1976, a beam of polarized light is directed through the aqueous humor of the person's eye to measure that person's blood glucose level. The fraction of this light that is absorbed during transit through that person's eye indicates the glucose level in the blood.
In U.S. Pat. No. 3,958,560 entitled Non-Invasive Automatic Glucose Sensor System, issued on May 25, 1976 to Wayne Front March, an infrared light source, mounted on a scleral contact lens, transmits 0.975 micron, infrared light through this contact wearer's cornea and aqueous humor to an infrared detector, also mounted on this lens. This wavelength is used because it is absorbed strongly by the hydroxyl in glucose. Test results are transmitted to a receiver mounted on or near this person, thereby providing nearly continuous monitoring of that person's blood glucose level. For example, a test can be initiated each time a person blinks.
In U.S. Pat. No. 4,014,321 entitled Non-invasive Glucose Sensor System issued to Wayne Front March on Mar. 29, 1977, a polarized beam of light is directed through a person's eye and the blood glucose level is determined from the amount that this polarized light is rotated by passage through this person's eye.
There are several disadvantages of using a person's eye as the target for blood glucose measurements. Considerable care must be exercised to prevent physical damage to the eye. The scleral contacts, containing blood chemistry test equipment, can be uncomfortable to the wearer. Professional care is required if insertion of an object into the eye is part of the measurement routine, such as is the case in U.S. Pat. No. 3,963,019 cited above. Such a blood glucose monitor would not be desirable for diabetic patients who have to measure their own blood glucose levels daily.
The following references describe blood glucose monitors that inject a beam of light through a person's skin to interact with the blood adjacent to the skin.
German Offenlegungsschrift DE 38 01 158 A1 entitled Blood Sugar Measuring Apparatus filed by Marina Struck on Jan. 16, 1988, is a rather confusing application, in which a monochromatic laser transmits a polarized, monochromatic, laser beam, through the skin of a person's finger, apparently for the purpose of rotating glucose molecules in the blood. There is some discussion of this light causing rotation of sugar molecules, some discussion of the polarization being caused by a reflection from the sugar molecules of a proper orientation, some discussion that photons are emitted from excited glucose molecules in the blood and some discussion that this light is tuned to a characteristic wavelength of glucose. This teaching appears to be inconsistent and is so confusing that it does not really teach the true nature of that invention.
In U.S. Pat. No. 4,901,728 entitled Personal Glucose Monitor issued to Donald P. Hutchinson on Feb. 20, 1990, two infrared beams are formed which are polarized, respectively, at +45.degree. and -45.degree. relative to a polarizer and, therefore, these two beams normally produce equal intensity output signals. However, when these beams are passed through a person's tissue, such as that person's ear lobe, these polarized beams are rotated by glucose by equal angles, thereby reducing the intensity of one of the output signals and increasing the other. These pulses are chopped so that the detector receives, at any given time, only light from one of these beams.
In recognition of the strong absorption of (long wavelength) infrared radiation by tissue and the effects of other variable parameters associated with tissue such as its thickness, pigmentation, temperature and blood volume etc., this reference recommends the use of two radiation sources which emit infrared light at two different wavelengths. Specifically, this reference uses light beams of wavelength 0.94 microns and 1.3 microns, in what is commonly referred to as the "near-infrared" region (i.e., wavenumber in the range 10,638-7,692 cm.sup.-1). Hutchinson's proposed intricate optical technique in the monitoring of blood glucose in tissue is rather complicated and requires a number of very delicate and difficult adjustments in its operation. It is therefore not readily amenable to the realization of a reliable, low-cost and rugged blood glucose sensor, such as is badly needed today. It is asserted, without discussion, that the use of an additional pair of analogous beams at different wavelengths enables correction for tissue absorption. U.S. Pat. No. 5,009,230 entitled Personal Glucose Monitor issued to Donald P. Hutchinson on Apr. 23, 1991, provides the missing details regarding this correction for tissue absorption.
The following references utilize absorption spectroscopy to detect various blood chemicals:
In the article by H. Zeller, et al entitled Blood Glucose Measurement by Infrared Spectroscopy, p. 129-134, (1989), the absorption spectra of blood glucose and some other blood components, are analyzed for the purpose of identifying those wavelength ranges in which accurate measurements of blood glucose can be detected. Differences between absorption spectra for a water-only solution and for a water-plus-glucose solution is observed only in an wavenumber range, referred to therein as the "finger-print region", which extends from 1650 to 800 cm.sup.-1.
A strong absorption peak, which occurs at a wavelength of 9.02 micron (i.e., wavenumber 1109 cm.sup.-1), is caused by the stretching vibrations of the endocyclic C--O--C group. Water absorption washes out all glucose spectra in the near infrared (NIR) (i.e., wavenumber in the range 12,500-4,000 cm.sup.-1) and the mid infrared (MIR) wavelength regions (i.e., wavenumber in the range 4,000-500 cm.sup.-1), so that, except for the finger-print region, these regions are not suitable for monitoring blood glucose levels. In the fingerprint region, only glucose and haemoglobin exhibit intense absorption at this wavelength. Only the following five wavenumbers give enough sensitivity for measurement of blood glucose: 1040, 1085, 1109, 1160 and 1365 cm.sup.-1. Only the 1040 cm.sup.-1 band is free of superimposed absorption of other blood constituents, and only glucose and haemoglobin exhibit intense absorption at 1109 cm.sup.-1. Therefore, the most attractive choices for monitoring blood glucose levels are the 1040 and 1109 cm.sup.-1 absorption bands.
In the article by Yitzhak Mendelson, et al entitled Blood Glucose Measurement by Multiple Attenuated Total Reflection and Infrared Absorption Spectroscopy, IEEE Transactions On Biomedical Engineering, Vol. 17, No. 5, May 1990, it is recognized that, of the more than 20 absorption peaks of D-glucose in the 2.5-10 micron range, not all of those peaks are specific to D-glucose. However, the peak at an wavenumber of 640 cm.sup.-1 is prominent and is due to the carbon-oxygen-carbon bond in the pyrane ring of D-glucose. It is also recognized that, because of the intrinsic high background absorption of water in the infrared wavelength range and the relatively low glucose concentrations in blood, it is important to use a CO.sub.2 laser, because it produces a powerful beam having a narrow peak that is effective in detecting such low concentrations. Sensitivity is further increased by using a multiple attenuated total reflection (ATR) to pass the laser beam through the sample several times. Unfortunately, equipment implementing such a laser/ATR technique is very expensive.
Biological molecules, due to their very complicated structures, possess a large number of similar infrared absorption peaks that are often overlapping. For example, the characteristic infrared spectrum of anhydrous D-glucose (ADG) has more than 20 absorption peaks in the wavelength region of 2.5-10 microns as shown in FIG. 1. It is important to note that not all the absorption peaks shown in FIG. 1 are specific to this molecule. The prominent absorption peak around 9.61 microns (1,040 cm.sup.-1), however, is somewhat specific to the carbon-oxygen--carbon bond of glucose, because of its pyrane ring.
In U.S. Pat. No. 5,028,787 entitled Non-invasive Measurement of Blood Glucose, issued to Robert D. Rosenthal on Jul. 2, 1991, a near-infrared quantitative analysis instrument and method are presented that non-invasively measures blood glucose by analyzing near-infrared energy following "interactance" with venous or arterial blood, or transmission through a blood containing body part, such as a finger tip. Because of the strong absorption of long wavelength, infrared radiation by body tissues, only near-infrared radiation of wavelength less than approximately one micron is used. A set of filters are utilized to pass through a sample only wavelengths that are much more strongly absorbed by glucose than by other interfering substances in the blood. The effect is that the interference from these other substances is substantially removed. Because Rosenthal has worked in this field since 1978 without yet producing a commercial non-invasive blood glucose monitor, it appears unlikely that this approach will be successful.
In a closely related U.S. Pat. No. 4,882,492 entitled Non-Invasive Near Infrared Measurement of Blood Analyte Concentration, issued to Kenneth J. Schlager on Nov. 21, 1989, an apparatus and related method are disclosed for measuring the concentration of glucose or other blood analytes utilizing both diffuse reflected and transmissive infrared absorption measurements. The wavelengths of exposing radiation are again limited to less than 2 microns. A high intensity light source is utilized as a source to provide sufficient light intensity to penetrate a significant distance into a blood sample. A cell containing only an interfering analyte is placed in the optical path to absorb substantially all of the light in interfering absorption bands, thereby substantially eliminating the interfering spectral components. This has the advantage of allowing transmission of bands of light, outside of those bands that are strongly absorbed by spectrally interfering substances in the blood. This allows more light to pass through the blood sample than is allowed in the Rosenthal approach that only passes a few narrow bands of light.
The same difficulty (i.e., high absorption of water in the wavelength range of exposing light) experienced by Rosenthal over the years in his proposed methods apply also to the teachings of Schlager. The prognosis of a breakthrough in the successful development of a non-invasive blood glucose monitor using near-infrared absorption and related techniques remains at present very much in doubt.
The use of infrared absorption spectroscopy for blood glucose measurement was proposed as early as 1981. This work was actively carried forward by a host of research scientists and physicians during the past decade leading to the above-indicated investigations by Zeller et. al. in 1989 and Mendelson et. al. in 1990. The motivation for such intense efforts in this particular field of research stems from the need for a convenient, inexpensive method of monitoring blood glucose concentration levels.
The use of glucose absorption bands in the near and middle infrared regions for continuous blood glucose measurement appeared very promising in the early years. However, the measurement of physiological concentrations of glucose in blood by conventional infrared absorption spectroscopy has been severely hampered by the intrinsic high background absorption of water in the infrared (see FIG. 2). Despite numerous proposals and attempts, no viable physical measurement technique has yet been developed, that would lead to the realization of a low-cost, non-invasive blood glucose sensor. The most recent proposal by Mendelson et. al. of using a carbon dioxide (CO.sub.2) laser as an infrared source in combination with a multiple attenuated total reflection (ATR) technique increases the depth of penetration of an optical beam into the sample, but does not overcome the fundamental problem that the absorption by water far exceeds the absorption by the blood component to be measured.
FIG. 2 illustrates that, in the near to medium infrared regions (i.e., 2-10 micron wavelength light), the absorption coefficient of water exceeds 10 cm.sup.-1 and reaches as high as 10,000 cm.sup.-1 at approximately 3 microns. For an absorption coefficient of 100 cm.sup.-1, 63% of infrared radiation would be absorbed by a mere 0.1 mm layer of water. Since over 80% (by weight) of the human body is water, any device that relies upon the absorption of infrared radiation by blood-glucose in some part of the human body containing blood, would receive too weak a signal to process. Although a high power CO.sub.2 laser, operating in the infrared wavelength region, can provide sufficient optical power to penetrate significantly through such a high absorbance medium, the cost of such a coherent source alone renders a low-cost, non-invasive blood-glucose sensor impractical. In addition, the absorption rate by the water in the blood greatly exceeds that for the blood glucose, so that the portion of the absorption signal caused by the blood glucose is much smaller than that for water. The CO.sub.2 laser does, however, enable the optical energy to be concentrated within the absorption peak of blood at 1040 cm.sup.-1, so that sensitivity is at least much better than when a broader band source is utilized. However, an effective blood glucose concentration detector should somehow overcome the above limitation of the blood glucose being much less absorptive in this range than is the water content of blood.